Gami-Chunggan Formula Prevents Motor Dysfunction in MPTP/p-Induced and A53T α-Synuclein Overexpressed Parkinson's Disease Mouse Model Though DJ-1 and BDNF Expression.

Sora Ahn,Guwon Jeong,Hi-Joon Park,Dong-Hee Kim,Ha Jin Jeong,Songhee Jeon,Youngman Kim,Jeonghun Park,Seung-Yeon Cho,Quan Feng Liu,Seung Tack Oh,Jae-Hwan Jang,Seong-Uk Park

doi:10.3389/fnagi.2019.00230

Abstract

The Gami–Chunggan formula (GCF) is a modification of the Chunggan (CG) decoction, which has been used to treat movement disorders such as Parkinson’s disease (PD) in Traditional East Asian Medicine. To evaluate the neuroprotective effects of GCF in chronic PD animal models, we used either a 5-week treatment of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine with probenecid (MPTP/p) or the α-synuclein A53T overexpressed PD mouse model. C57BL/6 mice were treated with MPTP, in combination with probenecid, for 5 weeks. GCF was administered simultaneously with MPTP injection for 38 days. The A53T α-synuclein overexpressed mice were also fed with GCF for 60 days. Using behavioral readouts and western blot analyses, it was observed that GCF prevents motor dysfunction in the MPTP/p-induced and A53T α-synuclein overexpressed mice. Moreover, GCF inhibited the reduction of dopaminergic neurons in the substantia nigra (SN) and fibers in the striatum (ST) against MPTP/p challenge. The expression of DJ-1 was increased but that of α-synuclein was decreased in the SN of PD-like brains by GCF administration. In vitro experiments also showed that GCF inhibited 6-OHDA-induced neurotoxicity in SH-SY5Y neuroblastoma cell lines and that it did so to a greater degree than CG. Furthermore, GCF induced BDNF expression through phosphorylation of Akt, ERK, CREB, and AMPK in the SN of PD-like brains. Therefore, use of the herbal medicine GCF offers a potential remedy for neurodegenerative disorders, including Parkinson’s disease.

Highlights

Parkinson’s disease (PD) is a chronic neurodegenerative disorder that is predominantly characterized by three representative motor features: akinesia, stiffness, and tremors (Conley and Kirchner, 1999; Kalia and Lang, 2015)
One reference compound from each plant source used in Gami–Chunggan formula (GCF) was selected for standardization based a thorough literature scan (Figure 1A; Yun et al, 2008; Tuan et al, 2012; Korean Food and Drug Administration [KFDA], 2015; Baek et al, 2016)
When the GCF extract samples were analyzed, their chromatograms showed eight peaks matching those of the eight reference compounds (Figure 1B)

Summary

Introduction

Parkinson’s disease (PD) is a chronic neurodegenerative disorder that is predominantly characterized by three representative motor features: akinesia, stiffness, and tremors (Conley and Kirchner, 1999; Kalia and Lang, 2015). MPTP targets dopaminergic neurons and causes severe and irreversible PD-like syndrome in non-human primates and humans. These subjects display biochemical and pathological hallmarks of PD (Przedborski et al, 2000) such as the obvious loss of dopaminergic neurons, astrogliosis, and activated microglia in the substantia nigra pars compacta (SNpc) (Beal, 2001). In the chronic MPTP/probenecid (MPTP/p) model, approximately 40–45% of dopaminergic neurons in the SNpc are lost within 3 weeks of treatment while 25% are lost in subchronic models without probenecid (Petroske et al, 2001; Meredith et al, 2008). Death of dopaminergic neurons continues for at least 6 months, unlike in the subchronic and acute MPTP models (Petroske et al, 2001; Meredith et al, 2008). 6-OHDA, on the other hand, mimics symptoms of PD by generating free radicals after it is transported by the dopamine transporter, resulting in the cell death of dopaminergic neurons

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